Depression is a state of persistent low mood, often with low self-esteem and a loss of interest in activities and experiences. It affects hundreds of millions of people worldwide; this pervasive condition affects the quality of life through emotional, cognitive, behavioral, and physical symptoms. Depression is the leading cause of disability, and can lead to suicide. [13, 15]
Physicians often prescribe selective serotonin reuptake inhibitors (SSRIs) to treat depression. These drugs work by preventing the reuptake of serotonin back into the synapse of a neuron, theoretically leaving more serotonin to bind to receptors. [1, 14] However, SSRIs are not effective for everyone, and many people experience adverse side effects. [2, 6, 10] Thus, practitioners and patients alike may search for other solutions. The underlying idea of targeting serotonin and the communication system of neurotransmitters by natural means may offer an alternative or complementary option.
Serotonin is an inhibitory neurotransmitter synthesized from tryptophan, an amino acid. It is found in the central nervous system (CNS), blood platelets, and most abundantly in the gut. Serotonin is involved in many body functions, including mood, sleep (as the precursor to melatonin), pain perception, hormone secretion, food intake, and cognitive function. This inhibitory neurotransmitter helps to promote calm, relaxation, and a sense of wellbeing. Serotonin also acts as a neuromodulator, able to reduce the release of glutamate, the main excitatory neurotransmitter, as well as stimulate the release of the main inhibitory neurotransmitter GABA. 
If the level or function in the body is insufficient, serotonin will not be able to work optimally in regulating excitation or stimulating GABA. Without serotonin’s modulation and inhibitory effects, excitatory neurotransmission (glutamate, dopamine, norepinephrine, epinephrine) may be in excess, causing over-excitation that could result in anxiety, irritability, poor memory, lack of focus, and poor sleep. People with low serotonin levels may experience increased depression, as well as anxiety, pain perception, carbohydrate cravings, and insomnia due to the low serotonin and GABA activity. Sufficient levels of serotonin in the body may help maintain balance between excitation/energy and inhibition/relaxation. 
Individuals with depression and low serotonin may benefit from supplementation to support serotonin. 5-HTP is a popular supplement for this use, as it is the direct precursor to serotonin in the serotonin biosynthetic pathway. Supplemental 5-HTP readily crosses the blood-brain barrier and increases CNS synthesis of serotonin. 5-HTP supplementation has been shown to be effective in reducing anxiety, increasing calmness, and promoting a sense of well-being. 
Additionally, some individuals may benefit from a supplement containing myo-inositol. Inositol is an isomer of glucose that we consume naturally in our diets. In the body, inositol is found in cell membranes. Inositol helps with the maintenance and effectiveness of cell signaling as part of the second messenger system. [7, 10] Inositol’s functions in cell communication is important because this second messenger system is associated with neurotransmitter pathways and receptors, including serotonin. Inositol may modulate the interaction between neurotransmitters, drugs, receptors, and signaling proteins. [3, 7] Inositol may also reverse desensitization of serotonin receptors, a common effect of SSRIs.  Research has shown that inositol may be beneficial for people with depression and bipolar depression, as well as anxiety, panic disorders, OCD, and other mood concerns. [3, 7, 10, 12]
St. John’s wort is an herb commonly used for depression. St. John’s wort inhibits the reuptake of neurotransmitters such as serotonin, GABA, and dopamine, leaving more of these neurotransmitters available for potential use. This herb can also increase neurotransmitter sensitivity. Better neurotransmission means that there could be more potential for the mood regulation and calming effects of serotonin and GABA. 
Individuals with depression may also consider a supplement containing vitamin B6. Vitamin B6 has a variety of positive health effects due to its involvement with neurotransmitters. In the active form of pyridoxal-5-phosphate, vitamin B6 is a cofactor in the serotonergic pathway. B6 supplementation can increase serotonin and dopamine, thus increasing the calming, pain-inhibiting, and pleasurable effects of these neurotransmitters.  Vitamin B6 has been found to decrease the severity of depression, as well as anxiety, headaches, and pain. [5, 16] Additionally, vitamin B6 may be even more effective in combination with calcium or magnesium supplementation. [5, 11]
Overall, serotonin plays a major role in maintaining balance within the body and regulating a variety of functions associated with depression. Before implementing or altering an intervention for depression, it is essential to first assess neurotransmitter levels to reveal any imbalances or deficiencies present. After introducing an appropriate intervention, such as 5-HTP supplementation, allowing adequate time for levels to replenish, it is also important to retest neurotransmitter levels to determine the effectiveness of the intervention in increasing serotonin and improving depression, and making any necessary adjustments to the individual’s therapy.
Following this model of testing and retesting, along with safe, effective therapies, may help people with depression understand underlying imbalances related to their experience, and offer evidence-based therapies that may be effective in managing depression and improving their quality of life.
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